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Marine Drugs marine drugs Article Neuroprotective Effect of Carotenoid-Rich Enteromorpha prolifera Extract via TrkB/Akt Pathway against Oxidative Stress in Hippocampal Neuronal Cells Seung Yeon Baek and Mee Ree Kim * Department of Food and Nutrition, Chungnam National University, Daejeon 34134, Korea; [email protected] * Correspondence: [email protected]; Tel.: +82-42-821-6837; Fax: +82-42-821-8887 Received: 27 June 2020; Accepted: 17 July 2020; Published: 19 July 2020 Abstract: In this study, we found that E. prolifera extract (EAEP) exhibits neuroprotective effects in oxidative stress-induced neuronal cells. EAEP improved cell viability as well as attenuated the formation of intracellular reactive oxygen species (ROS) and apoptotic bodies in glutamate-treated hippocampal neuronal cells (HT-22). Furthermore, EAEP improved the expression of brain-derived neurotrophic factor (BDNF) and antioxidant enzymes such as heme oxygenase-1 (HO-1), NAD(P)H quinine oxidoreductase-1 (NQO-1), and glutamate–cysteine ligase catalytic subunit (GCLC) via the tropomyosin-related kinase receptor B/ protein kinase B (TrkB/Akt) signaling pathway. In contrast, the pre-incubation of K252a, a TrkB inhibitor, or MK-2206, an Akt-selective inhibitor, ameliorated the neuroprotective effects of EAEP in oxidative stress-induced neuronal cells. These results suggest that EAEP protects neuronal cells against oxidative stress-induced apoptosis by upregulating the expression of BDNF and antioxidant enzymes via the activation of the TrkB/Akt pathway. In conclusion, such an effect of EAEP, which is rich in carotenoid-derived compounds, may justify its application as a food supplement in the prevention and treatment of neurodegenerative disorders. Keywords: Enteromorpha prolifera; oxidative stress; apoptosis; BDNF; TrkB/Akt pathway 1. Introduction In recent decades, the number of patients diagnosed with neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease, has increased continuously along with the extended lifespan and environmental pollution worldwide [1,2]. The pathophysiology of neurodegenerative diseases is closely related to the generation of reactive oxygen species (ROS), which results in protein and DNA damage, inflammation, tissue damage and subsequently induces apoptosis in neuronal cells [3,4]. Accordingly, one of the key neuroprotective strategies entails regulation of ROS generation in order to prevent or treat neurodegenerative diseases [5]. Another preventive and treatment strategy for neurodegenerative disease involves activating the production of brain-derived neurotrophic factor (BDNF) [6]. BDNF is released from the central nervous system and plays an important role in cell proliferation, protection, synaptic function, morphogenesis, and plasticity mediated via tropomyosin-related kinase receptor B (TrkB) [7,8]. Most studies investigating BDNF have reported that the expression of BDNF protects neuronal cells against oxidative stress and decreases the risk of neurodegenerative disorders in the brain [8,9]. Recent studies suggest that some natural antioxidant compounds suppress the oxidative stress induced by ROS and activate the BDNF/TrkB pathway in neuronal cells [9–11]. Marine seaweeds possess biochemical properties that may be exploited to develop therapeutic and functional foods. Marine seaweeds are considered an abundant source of antioxidants including flavonoids, phenolic compounds, carotenoids, and chlorophyll [12–15]. Enteromorpha prolifera (EP) Mar. Drugs 2020, 18, 372; doi:10.3390/md18070372 www.mdpi.com/journal/marinedrugs Mar. Drugs 2020, 18, 372 2 of 12 Marine seaweeds possess biochemical properties that may be exploited to develop therapeutic Mar. Drugs 2020, 18, 372 2 of 13 and functional foods. Marine seaweeds are considered an abundant source of antioxidants including flavonoids, phenolic compounds, carotenoids, and chlorophyll [12–15]. Enteromorpha prolifera (EP) belongs to the phylum phylum Chlorophyt Chlorophyta,a, class class Chlorophyceae, Chlorophyceae, order order UlvalesUlvales,, and and genus genus EnteromorphaEnteromorpha [16].[16]. It is is cultivated cultivated worldwide worldwide along along the the seashore seashore and and is used is used to treat to treat symptoms symptoms including including epistaxis epistaxis and signsand signs of inflammation of inflammation in eastern in eastern Asia Asia [17]. [17 ].Poly Polysaccharidessaccharides derived derived from from EP EP have have attracted attracted the attention of investigators involved in their identific identificationation and determination of structure and function including antioxidant,antioxidant, anti-inflammatory, anti-inflammatory, anti-diabetic, anti-diabetic, and anti-apoptoticand anti-apoptotic activities activities [17–20]. However,[17–20]. However,EP is a source EP is of a polysaccharides,source of polysaccharides, crude fiber crude and fib protein,er and asprotein, well as as unsaturated well as unsaturated fatty acids fatty such acids as suchlinoleic as linoleic acid, linolenic acid, linolenic acid, EPA, acid, DHA, EPA, minerals, DHA, mine andrals, vitamins and vitamins [21]. Furthermore, [21]. Furthermore, EP contains EP contains diverse phytochemicalsdiverse phytochemicals such as chlorophyll,such as chlorophyll, phycocyanin, phycocyanin, flavonoids, flavonoids, and phenolic and compounds, phenolic compounds, which affect whichthe antioxidant affect the activity antioxidant of the activity marine of algal the extract marine [22 algal,23]. extract The anti-diabetic [22,23]. The eff anti-diabeticect of flavonoids effect and of polyphenolsflavonoids and in thepolyphenols EP extract wasin the established EP extract in was the intestinalestablished microflora in the intestinal of type 2 microflora diabetic mice of [type24,25 2]. diabeticIn addition, mice in [24,25]. a previous In addition, report, we in investigated a previous thatreport, the antioxidantwe investigated activity that of the an ethylantioxidant acetate fractionactivity of an EP ethyl extract acetate (EAEP) fraction was stronger of EP extract than that(EAEP) of aqueous was stronger and 95%than ethanol that of aqueous extract [23 and]. In95% the ethanol report, weextract found [23]. that In the EAEP report, is rich we infound carotenoid-derived that EAEP is rich dihydroactinidiolide in carotenoid-derived and dihydroactinidiolide carotenoids including and carotenoidscanthaxanthin, including violaxanthin, canthaxant and fucoxanthin,hin, violaxanthin, which exhibit and potent fucoxa neuroprotectiventhin, which activity exhibit [23 ,potent26–29]. neuroprotectiveDespite extensive activity analyses [23,26–29]. of the EPDespite extract, extensiv few studiese analyses have of investigatedthe EP extract, the few antioxidant studies have and investigatedneuroprotective the eantioxidantffects associated and neuroprotectiv with phytochemicals.e effects associated with phytochemicals. In this study, we investigated the neuroprotectiv neuroprotectivee role of EAEP against oxidative stress-induced neurodegeneration in hippocampal neuronal cellscells (HT-22)(HT-22) mediatedmediated viavia TrkBTrkB/Akt/Aktpathway. pathway. 2. Results Results 2.1. Neuroprotective Neuroprotective Effect Effect of EAEP on Glutamate-InducedGlutamate-Induced Oxidative Stress in HT-22HT-22 CellsCells Glutamate isis an an excitatory excitatory neurotransmitter neurotransmitter in the centralin the nervous central system nervous [30]. Highsystem concentrations [30]. High concentrationsof glutamate inhibit of glutamate the uptake inhibit of Nthe-acetyl uptake cysteine, of N-acetyl which cysteine, results which in the results reduction in the in intracellularreduction in intracellularglutathione levelsglutathione and subsequent levels and subsequent oxidative stress oxidative associated stress withassociated cell death with suchcell death as apoptosis such as apoptosisand necrosis and [ 31necrosis]. First, [31]. we investigatedFirst, we invest whetherigated EAEPwhether prevented EAEP prev glutamate-inducedented glutamate-induced oxidative oxidativestress in hippocampal stress in hippocampal neuronal cellsneuronal because cells EAEP because has beenEAEP reported has been to reported exhibit high to exhibit antioxidant high antioxidantactivity [21,23 activity]. The incubation[21,23]. The of HT-22incuba cellstion withof HT-22 EAEP (10–100cells withµg /mL)EAEP prior (10–100 to glutamate μg/mL) treatment prior to glutamateimproved celltreatment viability improved up to a cell concentration viability up of to 100 a µconcentrationg/mL (Figure of?? 100A). Inμg/mL particular, (Figure exposure 1A). In particular,to EAEP 100 exposureµg/mL to completely EAEP 100 μ restoredg/mL completely cell viability restored to the cell same viability level to as the in same the controllevel as group.in the Ascontrol shown group. in Figure As shown??B, in glutamate-induced Figure 1B, glutamate- HT-22induced cells generatedHT-22 cells intracellular generated intracellular ROS. In contrast, ROS. InEAEP contrast, dose-dependently EAEP dose-dependently reduced the reduced intracellular the in ROStracellular level (Figure ROS level??B). (Figure These results 1B). These suggest results that suggestEAEP attenuated that EAEP neuronal attenuated cell deathneuronal against celloxidative death against stress byoxidative regulating stress ROS by generation. regulating Thus,ROS generation.EAEP may playThus, a EAEP neuroprotective may play a role neuroprotective in glutamate-induced role in glutamate-induced HT-22 cells. HT-22 cells. Figure 1. Effect of ethyl acetate extract
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